Use of dopamine receptor antagonists in combination with partial dopamine agonist to prevent tolerance in treating nervous disorders related to dopamine dysfunction

Abstract

Dopamine receptor antagonists are commonly prescribed for the treatment of schizophrenia and psychosis. While they are effective antipsychotics, they fail to treat other aspects of the disorder (e.g. negative symptoms, attention, and concentration) and have severe side effects, ranging from parkinsonism, acute motor side effects, akasthisia, dysphoria, and tardive dyskinesia. Dopamine agonist drug treatments are effective in treating both positive and negative symptoms without the common side effects. Unfortunately, dopamine agonists suffer from efficacy tolerance, the time limited effect on the order of 1-7 days. Thus, despite the partial effectiveness of current treatments, pressing need exists for new treatments. The combination drug therapy described herein meets this need. Specifically, the invention involves the use of small doses of dopamine receptor antagonists to reduce the intrinsic activity of a partial agonist, thereby reversing the agonist-induced tolerance commonly reported with agonist therapy alone.

What is claimed:  
     
         1 . A method for treating a central nervous disorder associated with dopamine dysfunction comprising: 
 (a) administration of a full or partial dopamine receptor agonist, to be administered in a amount reduce symptoms of said disorder, and    (b) co-administration of a dopamine receptor antagonist, said dopamine receptor antagonist being administered in an amount sufficient to reduce the intrinsic activity of the receptor agonist.    
     
     
         2 . The method of    claim 1   , wherein said receptor antagonist is haloperidol.  
     
     
         3 . The method of    claim 2   , wherein haloperidol is administered in a dose between about 0.1 mg and 1.5 mg, b.i.d.  
     
     
         4 . The method of    claim 2   , wherein the haloperidol is administered in a dose between about 0.2 mg and 1 mg b.i.d.  
     
     
         5 . The method of    claim 2   , wherein the haolperidol is administered in a dose between about 0.3 and 0.7 mg b.i.d.  
     
     
         6 . The method of    claim 1   , wherein said receptor antagonist is clozapine.  
     
     
         7 . The method of    claim 6   , wherein the clozapine is administered in a dose between about 10 mg and 80 mg b.i.d.  
     
     
         8 . The method of    claim 6   , wherein the clozapine is administered in a dose of between about 20 mg and 60 mg. b.i.d.  
     
     
         9 . The method of    claim 1   , wherein said receptor agonist is (−)-3-PPP.  
     
     
         10 . The method of    claim 9   , wherein the (−)-3-PPP is administered in a dose between about 200 and 800 mg b.i.d.  
     
     
         11 . The method of    claim 9   , wherein the (−)-3-PPP is administered in a dose between about 300 and 600 mg b.i.d.  
     
     
         12 . The method of    claim 9   , wherein the (−)-3-PPP is administered in a dose between about 400 and 500 mg b.i.d.  
     
     
         13 . The method of    claim 1   , wherein said receptor agonist is apomorphine.  
     
     
         14 . The method of    claim 13   , wherein the apomorphine is administered in a dose between about 0.2 mg and 6 mg b.i.d.  
     
     
         15 . The method of    claim 13   , wherein the apomorphine is administered in a dose of between about 0.4 mg and 4 mg b.i.d.  
     
     
         16 . The method of    claim 13   , wherein the apomorphine is administered in a dose between about 0.5 and 3 mg b.i.d.  
     
     
         17 . The method of    claim 1   , wherein said receptor agonist is NPA.  
     
     
         18 . The method of    claim 1   , wherein said receptor antagonist is one of the group of bromocryptine, lisuride, CF25397, lergotrile, and piribedil.  
     
     
         19 . The method of    claim 1   , wherein said central nervous disorder is psychosis.  
     
     
         20 . The method of    claim 19   , wherein said psychosis is schizophrenia.  
     
     
         21 . The method of    claim 1   , wherein said central nervous disorder is a motor disorder.  
     
     
         22 . A method for treating a central nervous system transmitter receptor disorder, said receptor comprising a receptor utilizing G proteins, comprising: 
 (a) administering a partial or full receptor agonist and    (b) co-administering a receptor antagonist, said receptor antagonist modifying said receptor agonist intrinsic activity.    
     
     
         23 . The method of    claim 22   , wherein said agonist receptor agonist is (−)-3-PPP  
     
     
         24 . The method of    claim 22   , wherein said (−)-3-PPP is administered in a dose of between about 300 and 600 mg b.i.d.  
     
     
         25 . The method of    claim 22   , wherein said (−)-3-PPP is administered in a dose between about 400-500 mg b.i.d.  
     
     
         26 . The method of    claim 22   , wherein said receptor agonist is apomorphine.  
     
     
         27 . The method of    claim 22   , wherein the receptor agonist is NPA.  
     
     
         28 . The method of    claim 22   , wherein said receptor antagonist is one of the group of haloperidol and clozapine.  
     
     
         29 . The method of    claim 22   , wherein said receptor is a dopamine receptor.  
     
     
         30 . The method of    claim 22   , wherein said receptor is a serotonin receptor.  
     
     
         31 . The method of    claim 22   , wherein said receptor is a norepinepinine receptor.  
     
     
         32 . The method of    claim 22   , wherein said receptor is an acetyl choline receptor.  
     
     
         33 . A pharmaceutical composition for the treatment of a disorder of the central nervous system; said disorder being treated by a modification of a dopamine receptor; said composition being administered at substantially the same dose during long term therapy comprising: a full or partial dopamine receptor agonist co administered with a dopamine receptor antagonist.  
     
     
         34 . The pharmaceutical composition of  33 , wherein the partial dopamine receptor agonist is (−)-3-PPP.  
     
     
         35 . The pharmaceutical composition of  33 , wherein the partial dopamine receptor is apomorphine.  
     
     
         36 . The pharmaceutical composition of  33 , wherein the partial dopamine receptor is NPA.  
     
     
         37 . The pharmaceutical composition of    claim 33   , wherein the dopamine receptor antagonist is haloperidol.  
     
     
         38 . The pharmaceutical composition of    claim 33   , wherein the dopamine receptor antagonist is chlorpromazine.  
     
     
         39 . The pharmaceutical composition of    claim 33   , wherein the central nervous system disorder is psychosis.  
     
     
         40 . The pharmaceutical composition of    claim 33   , wherein the central nervous system disease is a movement disorder.